Microtubules are intracellular, filamentous, polymeric structures, present in eukaryotic cells, that extend throughout the cytoplasm and govern the location of membrane-bounded organelles and other cell components. Microtubules are involved in many cellular functions including chromosome migration during mitosis, organelle transport, cytokinesis, cell plate formation, cell motility, and maintenance of cell shape. Microtubules are composed of molecules of tubulin protein, each molecule of which is a heterodimer of α-tubulin and β-tubulin.
Mitosis is the process by which eukaryotic cells ensure the distribution of their chromosomes into two daughter cells during cell division. During this process, the cytoplasmic microtubules are disrupted and reformed as a (mitotic) spindle consisting of large numbers of short microtubules that surround each centrosome. As mitosis proceeds, the elongating ends of the microtubules attach to the chromosomes, the chromosomes align on the metaphase plate, and, during anaphase, the sister chromatids are separated. If any of these stages of chromosomal alignment and separation is disrupted by irregular microtubules, mitosis fails.
Implicit in this mechanism of microtubule-based chromosome migration and separation is that microtubules are labile structures. Further, that lability is critical for their function. The lability manifests through rapid polymerization and depolymerization of the microtubules, which enables cell-scale movements of the chromosomes during mitosis. Even when the mitotic spindle, and the microtubules from which it is made, appears macroscopically inert, tubulin subunits freely exchange on the microtubules. If such free exchange of tubulin subunits is disrupted, the mitotic spindle is compromised and the cell cannot divide. Certain drugs exploit the necessity of tubulin free-exchange in mitosis and act therapeutically by disrupting the delicate balance between microtubule polymerization and depolymerization. Some drugs bind to tubulin subunits, preventing them from being incorporated into a growing microtubule while others bind to the microtubule itself, preventing additional tubulin subunits from binding. As a consequence of either activity, cells undergoing division, and particularly those cells demonstrating aberrant, rapid division, i.e., cancer cells, are killed.
Anticancer drugs that act by binding to tubulin or to microtubules include the alkaloids vincristine and vinblastine, and the taxane-based compounds paclitaxel and docetaxel (see, for example, E. K. Rowinsky and R. C. Donehower, Pharmacology and Therapeutics, 52, 35–84 (1991)). Other antitubulin compounds active against mammalian cells include benzimidazoles such as nocodazole and natural products such as colchicine.
There remains a need in the art for effective, minimally toxic, easily obtained, cytotoxic agents for use in cancer therapy. There remains a need in the art for chemical compounds capable of inhibiting cellular mitosis for use in cancer therapy. Further there remains a need in the art for pharmaceutical compositions for use in cancer therapy. Still further, there remains a need in the art for methods of inhibiting microtubule polymerization and methods of cancer therapy. The present invention provides such embodiments.